Numerically Improved pCR Not Significant With SD-101 Plus Pembrolizumab in HER2– Breast Cancer


Some improvement in pathological complete response may be possible with SD-101 plus pembrolizumab and paclitaxel in certain patients with HER2-negative breast cancer, but results are still uncertain.

Patients with high-risk, HER2-negative, stage II/III breast cancer who were treated with intratumoral SD-101 plus pembrolizumab (Keytruda) and paclitaxel showed numerical improvement in estimated pathological complete response (pCR) rates in findings from the phase 2 I-SPY 2 trial (NCT01042379) presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, but these failed to meet statistical significance.1

SD-101 is a CpG-C class oligonucleotide that works by binding and activating toll-like receptor 9 in plasmacytoid dendritic cells. This leads to the stimulation of cytotoxic T cells. When SD-101 is administered intratumorally, it targets tumor-reactive T cells, specifically.

Multiple prior studies served as the rationale for the investigation of SD-101 with pembrolizumab and chemotherapy in early-stage, high-risk, HER2-negative breast cancer. First, an earlier branch of the I-SPY 2 trial showed that pCR rates nearly tripled in patients with hormone receptor (HR)–positive, triple-negative breast cancer (TNBC).2 Improvement in pCR was also demonstrated in the patients with TNBC treated with pembrolizumab plus neoadjuvant chemotherapy in the KEYNOTE-522 study (NCT03036488).3

“Preclinical data suggest a synergistic interaction between SD-101 and anti–PD-1 therapy. In anti–PD-1–resistant tumors, intratumoral SD-101 monotherapy results in transient tumor growth inhibition but does not result in durable tumor rejection. However, when combined with anti–PD-1 therapy, durable—often complete—tumor rejection is seen in both injected as well as non-injected distant tumors, suggesting systemic immunity,” said Amy Jo Chein, MD, associate clinical professor, Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, during the ASCO presentation.

Finally, in a 2018 study of SD-101 in combination with pembrolizumab as treatment of patients with advanced melanoma, investigators found that response rates were high and the combination led to changes in the local tumor microenvironment without showing any new safety signals.4

In I-SPY 2, patients who either had HR-positive and HER2-negative disease, or HR-negative and HER2-negative (TNBC), and a tumor larger than 2.5 cm, were adaptively randomized to receive either paclitaxel with SD-101 and pembrolizumab in the investigational arm or weekly paclitaxel for 12 weeks in the control arm. The 2 groups were explored separately as well as a third group of all HER2-negative breast cancers. Intravenous paclitaxel was administered at 80 mg/m2, SD-101 was administered at 2 or 4 mg by intratumoral injection depending on the tumor size, and pembrolizumab was dosed at 200 mg given intravenously. Treatment in either the experimental or control arm was followed by doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 given every 2 to 3 weeks for 8 to 12 weeks.1

Chein et al predicted at least an 85% probability of success in a neoadjuvant trial consisting of 300 patients. Graduation of the agent to a phase 3 study was assessed for each biomarker signature.

The trial started with a safety run-in analysis to test the use of 2 mg of SD-101 versus 4 mg in combination with pembrolizumab and paclitaxel. Based on the analysis, the volume of SD-101 was decreased according to tumor size from T3 or T4 to T2 or smaller. No new safety signals were observed with SD-101 plus pembrolizumab and paclitaxel in these patients.

Baseline demographics showed no statistical difference between the 2 treatment arms. All patients enrolled in the study had HER2-negative disease. In total, 75 patients were included in the SD-101 combination arm and 329 were included in the control arm. In the SD-101 arm, the median age was 48 years (range, 21-71). The arm was 80% White, 12% African American, and 8% Asian. In terms of HR status, 61% of the experimental arm was positive and 39% were negative. The median tumor size in the arm was 4.3 cm with the majority of patients having T2 tumors (63%). Palpable nodes were found in 29% of the arm.

The median age of patients in the control arm was also 48 years (range, 19-80). The group of patients was 77% White, 14% African American, 7% Asian, and 1% identified as another race. Fifty-five percent of the control arm had HR-positive tumors, and 45% had HR-negative tumors. The median tumor size was 3.8 cm in this arm with 68% of patients having a T2 tumor. Thirty-six percent of patients had palpable nodes.

Efficacy observed in the overall population of patients with HER2-negative breast cancer showed a 34% estimated pCR rate (0.341; 95% probability interval [PI], 0.24-0.44) with SD-100 plus pembrolizumab and paclitaxel versus 20% (0.199; 95% PI, 0.16-0.24) in the control arm. The probability that the SD-101 combination was superior to the control was 0.997, and the predictive probability of its success compared with the control in a phase 3 trial was 0.717.

Among the subset of patients whose biomarker signature was HR-negative and HER2-negative, the estimated pCR rate increased to 44% (0.437; 95% PI, 0.28-0.6) with the SD-101 combination from 28% (0.275; 95% PI, 0.21-0.34) with the control treatment, resulting in a 0.973 probability that experimental regimen has superiority over the control. The predictive probability of success with SD-101 plus pembrolizumab and paclitaxel in a phase 3 study over the control was 0.707.

Patients whose biomarker signature was HR-positive and HER2-negative achieved a pCR rate of 26% (0.259; 95% PI, 0.14-0.37) on treatment with the SD-101 combination compared with 14% (0.135; 95% PI, 0.09-0.18) in the control arm for a 0.986 probability that the experimental regimen is superior to the control therapy. This resulted in a 0.679 predictive probability of success in a phase 3 trial.

Response to therapy in the study was assessed by residual cancer burden (RCB).

“RCB 0 and 1 is prognostic for improved relapse-free survival compared to RCB 2 and 3. In particular, we were interested to see if SD-101 and pembrolizumab can shift the distribution of RCB class from RCB 2 and 3 to more RCB 0 and 1s,” explained Chein during the presentation of the study results. “In the hormone receptor–positive, HER2-negative signature, there was a shift from RCB 2 and 3 diseases to more RCB 0 and 1s relative to the control. However, this shift was not seen in the triple-negative signature,” she added.

Safety assessed in all patients treated in the study showed that notable treatment-related adverse events (TRAEs) in the experimental arm versus the control arm categorized as blood and lymphatic system disorders were most commonly any-grade febrile neutropenia (12% vs 6.4%) as well as neutropenia (41.3% vs 14.3%). Those TRAEs classified as general disorders in the experimental arm versus the control arm included injection site reactions (22.7% vs 1.5%), fever (58.7% vs 11.2%), and flu-like symptoms (12% vs 5.2%). In addition, skin and soft tissue infections in the experimental arm compared with the control arm were observed in 16% versus 2.7%, respectively.

Immune-related AEs (irAEs) were observed in 35% of the patients treated with the SD-101 combination. The most common irAEs were adrenal insufficiency in 12%, rash in 9.3%, pneumonitis in 6.7%, and hypothyroidism in 6.7%. Ninety-two percent of the patients who experienced rash, pneumonitis, or colitis were treated with systemic steroids. Notably, 58% of the irAEs occurred during docetaxel/cyclophosphamide treatment, and this timing was consistent with what was previously observed in the I-SPY 2 trial.

Between the 2 treatment arms, there were similar rates of discontinuation; however, the experimental arm showed higher rates of missed doses and dose delays. For this portion of the analysis, the investigators evaluated 73 patients from the experimental arm versus 323 from the control arm. Early discontinuation occurred in 11.1% versus 12.4%, respectively. Dose reduction alone with missed doses and delays were predominantly seen with paclitaxel. Chein stated that this increased number of dose interruptions was likely related to the higher percentage of irAEs in the experimental arm.

A prespecified analysis of the I-SPY 2 trial also looked at the association of MammaPrint (MP) class, a genomic test for relapse risk, and response to SD-101 plus pembrolizumab and paclitaxel.

“Since nearly all triple-negative cancers are MP 2, the analysis was focused on the hormone receptor–positive, HER2-negative subset where 33% are MP 2 as seen in other I-SPY immuno-oncology arms. The benefit of SD-101 was predominantly observed in MP 2 tumors with MP 1 tumors less likely to benefit,” explained Chein.

To conclude the presentation, Chein compared prior I-SPY 2 results with the results from the current analysis.

“It appears that adding SD-101 to pembrolizumab did not further increase the response in hormone receptor–positive, HER2-negative tumors, whether MP 1 or MP 2, nor did it improve response in the triple-negative subset,” Chein concluded.

A further look at biomarkers in this patient population is needed to identify patients who are most likely to benefit from SD-101 added to pembrolizumab. More research around this topic may also inform on how to best combine immunotherapy with chemotherapy in the future, according to the presentation.


1. Chein AJ, Soliman HS, Ewing CA, et al; I-SPY 2 TRIAL Consortium. Evaluation of intra-tumoral (IT) SD-101 and pembrolizumab (Pb) in combination with paclitaxel (P) followed by AC in high-risk HER2-negative (HER2-) stage II/III breast cancer: Results from the I-SPY 2 trial. J Clin Oncol. 2021;39(suppl 15; abstr 508). doi:10.1200/JCO.2021.39.15_suppl.508

2. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650.

3. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J . 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

4. Ribas A, Medina T, Kumma S, et al. SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. Cancer Discov. 2018;8(10):1250-1257. doi:10.1158/2159-8290.CD-18-0280.

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